A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis.

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

The liver-derived exosomes stimulate insulin gene expression in pancreatic beta cells under condition of insulin resistance.

Introduction: An insufficient functional beta cell mass is a core pathological hallmark of type 2 diabetes (T2D). Despite the availability of several effective pharmaceuticals for diabetes management, there is an urgent need for novel medications to protect pancreatic beta cells under diabetic conditions. Integrative organ cross-communication controls the energy balance and glucose homeostasis. The liver and pancreatic islets have dynamic cross-communications where the liver can trigger a compensatory beta cell mass expansion and enhanced hormonal secretion in insulin-resistant conditions. However, the indispensable element(s) that foster beta cell proliferation and insulin secretion have yet to be completely identified. Exosomes are important extracellular vehicles (EVs) released by most cell types that transfer biological signal(s), including metabolic messengers such as miRNA and peptides, between cells and organs. Methods: We investigated whether beta cells can take up liver-derived exosomes and examined their impact on beta cell functional genes and insulin expression. Exosomes isolated from human liver HepG2 cells were characterized using various methods, including Transmission Electron Microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis of exosomal markers. Exosome labeling and cell uptake were assessed using CM-Dil dye. The effect of liver cell-derived exosomes on Min6 beta cells was determined through gene expression analyses of beta cell markers and insulin using qPCR, as well as Akt signaling using Western blotting. Results: Treatment of Min6 beta cells with exosomes isolated from human liver HepG2 cells treated with insulin receptor antagonist S961 significantly increased the expression of beta cell markers Pdx1, NeuroD1, and Ins1 compared to the exosomes isolated from untreated cells. In line with this, the activity of AKT kinase, an integral component of the insulin receptor pathway, is elevated in pancreatic beta cells, as represented by an increase in AKT's downstream substrate, FoxO1 phosphorylation. Discussions: This study suggests that liver-derived exosomes may carry a specific molecular cargo that can affect insulin expression in pancreatic beta cells, ultimately affecting glucose homeostasis.

Abnormal acinar-ß-cell crosstalk in type 2 diabetes.

Cellular crosstalk plays a vital role in maintaining pancreas homeostasis. Recently, in Cell Metabolism, Basile et al. demonstrated that aberrant upregulation of acinar-cell-specific pancreatic elastase CELA3B within endocrine islets reduces ß-cell viability in type 2 diabetes (T2D). This identifies detrimental acinar-ß-cell crosstalk as a novel pathogenic mechanism in diabetes.

Correction: Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes.

[This corrects the article DOI: 10.1371/journal.pone.0161834.].

Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer.

A critical decline of functional insulin-producing pancreatic ß-cells is the central pathologic element of both type 1 and type 2 diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key mediator of ß-cell failure and the identification of neratinib as MST1 inhibitor with potent effects on ß-cell survival represents a promising approach for causative diabetes therapy. Here we report a case of robust glycemia and HbA1c normalization in a patient with breast cancer-T2D comorbidity under neratinib, a potent triple kinase inhibitor of HER2/EGFR and MST1. The patient, aged 62 years, was enrolled in the plasmaMATCH clinical trial and received 240 mg neratinib once daily. Neratinib therapy correlated with great improvement in glucose and HbA1c both to physiological levels during the whole treatment period (average reduction of random glucose from 13.6 ± 0.4 to 6.3 ± 0.5 mmol/l and of HbA1c from 82.2 ± 3.9 to 45.6 ± 4.2 mmol/mol before and during neratinib). 18 months later, when neratinib was withdrawn, random glucose rapidly raised together with high blood glucose fluctuations, which reflected in elevated HbA1c levels. This clinical case reports the combination of HER2/EGFR/MST1-inhibition by neratinib for the pharmacological intervention to effectively restore normoglycemia in a patient with poorly controlled T2D and suggests neratinib as potent therapeutic regimen for the cancer-diabetes comorbidity.

MST1 deletion protects ß-cells in a mouse model of diabetes.

The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic ß-cell mass as a result of improved ß-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of ß-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced ß-cell mass and improved insulin secretion without changes in insulin sensitivity. Metabolic and morphological data suggest that normalization of blood glucose and insulin secretion, islet architecture, and ß-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved ß-cell survival and proliferation establishing MST1 as potent regulator of physiological ß-cell turnover.

How ß cells can smell insulin fragments.

In this issue of Cell Metabolism, Cheng et al. identify olfactory receptor Olfr109 in ß cells with increased expression in islets from mouse models of obesity and type 1 and type 2 diabetes. Binding of a small insulin fragment to Olfr109 fosters islet inflammation, ß cell failure, and diabetes progression.

Treatment of Allergic Patients with Adenotonsillar Hypertrophy: Surgery Versus Medication Therapy:.

BACKGROUND: Adenotonsillar hypertrophy (AH) is the most common cause of respiratory obstruction of the upper airway, and tonsillectomy is one of the most frequently performed surgical interventions in children. It has been proposed that medical treatment in an allergic state could decrease the size of AH. Therefore, this study aimed to compare the outcomes of surgery and medical therapies among allergic children with AH. MATERIALS AND METHODS: This case-control study was carried out on 68 children with AH in an allergic state who were referred to the Pediatrics Hospital of Tabriz Medical University. They were divided into two groups and matched according to sex, age, and primary clinical signs and symptoms. Patients received surgery (case group) and medication (control groups) for treated AH. Finally, they were compared according to the results of treatment and recurrence rate. RESULTS: The mean age of children in the case and control groups was 6.3±2.3 and 6.8±2.1 years, respectively. There was no significant difference in improving clinical signs and symptoms between the two groups. In the case group, no improvement of clinical signs and symptoms was observed in one patient compared with two patients in the control group. In the control group, no decrease in the size of the tonsils was observed in three patients. Recurrence of clinical signs of AH was observed in six (17.6%) patients of the control group, and there was a significant difference between the two groups (P0.001). CONCLUSION: Our findings showed no significant differences in the outcomes of the two therapeutic methods for AH in an allergic state. However, medical treatment needs a long time to affect, but surgery can act quickly. Recurrence of AH after medical therapy could occur.

Deathly triangle for pancreatic ß-cells: Hippo pathway-MTORC1-autophagy.

A progressive decline in the macroautophagic/autophagic flux is a hallmark of pancreatic ß-cell failure in type 2 diabetes (T2D) but the responsible intrinsic factors and underlying molecular mechanisms are incompletely understood. A stress-sensitive multicomponent cellular loop of the Hippo pathway kinase LATS2 (large tumor suppressor 2), MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) and autophagy regulates ß-cell survival and metabolic adaptation. Chronic metabolic stress leads to LATS2 hyperactivation which then induces MTORC1, subsequently impairing the cellular autophagic flux and consequently triggering ß-cell death. Reciprocally, under physiological conditions, autophagy controls ß-cell survival by lysosomal degradation of LATS2. These signaling cross-talks and the interaction between autophagy and LATS2 are important for the regulation of ß-cell turnover and functional compensation under metabolic stress.

The Hippo kinase LATS2 impairs pancreatic ß-cell survival in diabetes through the mTORC1-autophagy axis.

Diabetes results from a decline in functional pancreatic ß-cells, but the molecular mechanisms underlying the pathological ß-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces ß-cell apoptosis and impaired function. LATS2 deficiency in ß-cells and primary isolated human islets as well as ß-cell specific LATS2 ablation in mice improves ß-cell viability, insulin secretion and ß-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in ß-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates ß-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating ß-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic ß-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic ß-cell survival and function in diabetes.

Inhibition of PHLPP1/2 phosphatases rescues pancreatic ß-cells in diabetes.

Pancreatic ß-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to ß-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic ß-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate ß-cell death. PHLPPs directly dephosphorylate and regulate activities of ß-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control ß-cell apoptosis. Genetic inhibition of PHLPPs markedly improves ß-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic ß cells in diabetes.

SARS-CoV-2 and pancreas: a potential pathological interaction?

The widespread extrapulmonary complications of coronavirus disease 2019 (COVID-19) have gained momentum; the pancreas is another major target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we take a closer look into potential pathological interactions. We provide an overview of the current knowledge and understanding of SARS-CoV-2 infection of the pancreas with a special focus on pancreatic islets and propose direct, indirect, and systemic mechanisms for pancreas injury as result of the COVID-19-diabetes fatal bidirectional relationship.

LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes.

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult ß-cell within the pancreatic islets. The repression of LDHA under normal physiological condition and its inappropriate upregulation under a diabetogenic environment is well-documented in rodent islets/ß-cells but little is known about LDHA expression in human islet cells and whether its abundance is altered under diabetic conditions. Analysis of public single-cell RNA-seq (sc-RNA seq) data as well as cell type-specific immunolabeling of human pancreatic islets showed that LDHA was mainly localized in human α-cells while it is expressed at a very low level in ß-cells. Furthermore, LDHA, both at mRNA and protein, as well as lactate production is upregulated in human pancreatic islets exposed to chronic high glucose treatment. Microscopic analysis of stressed human islets and autopsy pancreases from individuals with type 2 diabetes (T2D) showed LDHA upregulation mainly in human α-cells. Pharmacological inhibition of LDHA in isolated human islets enhanced insulin secretion under physiological conditions but did not significantly correct the deregulated secretion of insulin or glucagon under diabetic conditions.

STRIPAK Is a Regulatory Hub Initiating Hippo Signaling.

Signaling modules that integrate the diverse extra- and intracellular inputs to the Hippo pathway were previously unknown. By biochemical and molecular interrogation, Chen et al. established a molecular framework, the RhoA-RHPN-NF2/Kibra-STRIPAK axis, that regulates the status of Hippo core kinases and connects upstream signals to initiate and orchestrate the Hippo pathway.

Loss of TAZ Boosts PPARγ to Cope with Insulin Resistance.

In this issue of Cell Metabolism, El Ouarrat et al. identify the Hippo signaling terminal effector TAZ as an endogenous negative regulator of PPARγ, a master transcriptional regulator of lipid metabolism and insulin sensitivity. Selective destruction of TAZ in adipocytes lowers inflammation and restores insulin sensitivity and glucose homeostasis.